EP3505613B1 - Cell culture module, cell culture system and cell culture method - Google Patents
Cell culture module, cell culture system and cell culture method Download PDFInfo
- Publication number
- EP3505613B1 EP3505613B1 EP18213492.4A EP18213492A EP3505613B1 EP 3505613 B1 EP3505613 B1 EP 3505613B1 EP 18213492 A EP18213492 A EP 18213492A EP 3505613 B1 EP3505613 B1 EP 3505613B1
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- EP
- European Patent Office
- Prior art keywords
- cell culture
- fixer
- module
- sheet
- carrier member
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Images
Classifications
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- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/02—Form or structure of the vessel
- C12M23/04—Flat or tray type, drawers
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M21/00—Bioreactors or fermenters specially adapted for specific uses
- C12M21/18—Apparatus specially designed for the use of free, immobilized or carrier-bound enzymes
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/02—Form or structure of the vessel
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/22—Transparent or translucent parts
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/44—Multiple separable units; Modules
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/58—Reaction vessels connected in series or in parallel
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
- C12M25/02—Membranes; Filters
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
- C12M25/14—Scaffolds; Matrices
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M33/00—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M37/00—Means for sterilizing, maintaining sterile conditions or avoiding chemical or biological contamination
- C12M37/04—Seals
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M39/00—Means for cleaning the apparatus or avoiding unwanted deposits of microorganisms
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
- C12M41/46—Means for regulation, monitoring, measurement or control, e.g. flow regulation of cellular or enzymatic activity or functionality, e.g. cell viability
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/0068—General culture methods using substrates
- C12N5/0075—General culture methods using substrates using microcarriers
Definitions
- US 2017/166859 A1 discloses a cell culture carrier module, a bioreactor and a cell recovery method.
- the cell culture carrier module includes at least one cell culture carrier capable of transforming between a two dimensional structure and a three dimensional structure.
- the cell culture carrier exhibits the two dimensional structure in a loosened state and exhibits the three dimensional structure in a compressed state.
- a cell culture system includes a cell tank, a culture medium module and a cell culture module.
- the cell tank and the culture medium module respectively communicate with the cell culture module and the cell culture module includes a casing, a first fixer, a second fixer and a sheet-shaped carrier member.
- the casing has a chamber and at least one inlet/outlet. The inlet/outlet communicates with the chamber.
- the first fixer is fixed to the casing and located in the chamber.
- the second fixer is disposed in the chamber and is movable relative to the first fixer.
- the sheet-shaped carrier member is formed by arranging a plurality of cell culture carriers and two opposite ends of the sheet-shaped carrier member are respectively fixed to the first fixer and the second fixer.
- the sheet-shaped carrier member is in an open state or a folded state according to a variation in a distance between the first fixer and the second fixer due to a movement of the second fixer.
- FIG. 1A and FIG. 1B are respectively schematic views of cell culture carriers of a cell culture module in a twisted state and an untwisted state according to an example not part of the present invention.
- a cell culture module 100A of the present example includes a reactor 110, a first fixer 120, a second fixer 130A and a plurality of cell culture carriers 140.
- the reactor 110 has a chamber C10 and at least one inlet/outlet T12.
- the chamber C10 is configured to provide space for culturing cells.
- the inlet/outlet T12 communicates with the chamber C10.
- the first fixer 120 is fixed to the reactor 110 and located in the chamber C10.
- the cell culture carriers 140 are rendered in the untwisted state, as shown in FIG. 1B .
- the cells may be detached from the cell culture carriers 140 during a change of state of the cell culture carriers 140 from the twisted state to the untwisted state by the action of a substance such as an enzyme which may detach the cells from the cell culture carriers 140.
- a substance such as an enzyme which may detach the cells from the cell culture carriers 140.
- an enzyme or the like may act on cells inside the cell culture carriers 140 which are previously difficult to be acted upon by the enzyme, which conduces to enhancement of a cell recovery rate.
- the second fixer 130A is movably disposed in the chamber C10, when the reactor 110 is placed in the state of FIG. 1A , the second fixer 130A moves downward to a position close to the first fixer 120 due to its own gravity.
- the reactor 110 may be placed upside down as shown in FIG. 1B and changed to a state opposite the state in FIG. 1A .
- the second fixer 130A moves downward to a position away from the first fixer 120 due to its own gravity, and the cell culture carriers 140 are stretched by the first fixer 120 and the second fixer 130A and changed to the untwisted state.
- a weight block may be installed onto the second fixer 130A to ensure that the second fixer 130A may move by its own gravity.
- each of the cell culture carriers 140 is equivalent to a two-dimensional structure.
- the interleaved cell culture carriers 140 are equivalent to a three-dimensional structure.
- each of the cell culture carriers 140 in the twisted state has a regular spiral shape.
- the cell culture carrier 140 may also be randomly twisted, and thus a plurality of cell culture carriers 140 in the twisted state may have a coiling shape.
- the disclosure is not limited thereto.
- a material of the cell culture carriers 140 includes, for example, polyester (PET), nylon, polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC), polystyrene (PS), polycarbonate (PC), ethylene vinyl acetate (EVA), polyurethane (PU) or the like.
- PET polyester
- PE polyethylene
- PP polypropylene
- PVC polyvinyl chloride
- PS polystyrene
- PC polycarbonate
- EVA ethylene vinyl acetate
- PU polyurethane
- each of the cell culture carriers 140 may be in the shape of a striped sheet, a threadlike sheet, or in any other suitable shape.
- the inlet/outlet T12 of the cell culture module 100A may be disposed on one end portion of the reactor 110.
- the inlet/outlet T12 may be used both for entry and exit of a liquid such as a culture medium and a buffer solution and for cell collection.
- the entry and exit of the culture medium and the buffer solution and the cell collection may respectively use different channels, in view of preventing the whole module from contamination.
- the cell culture module 100A of the present example may include a plurality of inlets/outlets T12, T14, T16, T18 (not illustrated), T21 and T23, wherein the inlet/outlet T12 is disposed on one end portion of the reactor 110 and enables the cell collection.
- the inlets/outlets T14, T16 and T18 may be disposed on a side surface of the reactor 110 and close to the end portion of the reactor 110 on which the inlet/outlet T12 is disposed, so as to allow entry of different buffer solutions and culture media into the reactor 110.
- the numbers of the inlets/outlets T14, T16 and T18 may vary depending on the type and requirements of the actually injected liquid, and are not limited to those mentioned herein.
- FIG. 2A and FIG. 2B are schematic views of a cell culture carrier of a cell culture module, in the untwisted state and the twisted state, respectively, according to another example not part of the present invention.
- a cell culture module 100B of the present example is similar to the cell culture module 100A of FIG. 1A . Nonetheless, it should be noted that the cell culture module 100B of the present example further includes a magnetic control part 160A.
- a second fixer 130B of the present example has magnetism. Accordingly, the magnetic control part 160A may control the second fixer 130B to move, using magnetic force such as magnetic attractive force or magnetic repulsive force. As shown in FIG.
- the magnetic control part 160A when the magnetic control part 160A magnetically controls the second fixer 130B to move to a position away from the first fixer 120, the cell culture carriers 140 are rendered in the untwisted state.
- FIG. 2B when the magnetic control part 160A controls the second fixer 130B to move to a position close to the first fixer 120, the cell culture carriers 140 are rendered in the twisted state.
- the shape of the magnetic control part 160A of the present example roughly matches the shape of the reactor 110.
- the magnetic control part 160A itself is movable, thereby driving the second fixer 130B to move.
- the disclosure is not limited thereto.
- FIG. 3 is a schematic view of a cell culture module according to still another example not part of the present invention.
- a cell culture module 100C of the present example is similar to the cell culture module 100B of FIG. 2A .
- the magnetic control part 160B directly moves to one side of the reactor 110 away from the first fixer 120 and then uses magnetic force to attract the second fixer 130B to move to a position away from the first fixer 120.
- the second fixer 130B will move to a position close to the first fixer 120 due to its own gravity.
- FIG. 4A and FIG. 4B are schematic views of a cell culture carrier of a cell culture module, in the twisted state and the untwisted state, respectively, according to yet still another example not part of the present invention.
- a cell culture module 100D of the present example is similar to the cell culture module 100A of FIG. 1A . Nonetheless, it should be noted that the cell culture module 100D of the present example further includes a fastener 170.
- a reactor 110A further includes an elastic corrugated structure 110A1. When no force is applied thereto, the elastic corrugated structure 110A1 is, for example, in a stretched state as shown in FIG. 4B .
- the fastener 170 is configured to control the elastic corrugated structure 110A1 to remain in a compressed state or not, so that the elastic corrugated structure 110A1 may switch between the stretched state as shown in FIG. 4B and the compressed state as shown in FIG. 4A .
- a second fixer 130C of the present example is fixed to the reactor 110A, and the elastic corrugated structure 110A1 is located between the first fixer 120 and the second fixer 130C.
- the fastener 170 is fastened, the elastic corrugated structure 110A1 is in the compressed state.
- the first fixer 120 and the second fixer 130C approach each other to render the cell culture carriers 140 in the twisted state.
- the fastener 170 is released, the elastic corrugated structure 110A1 is in the stretched state.
- the controller 800 is connected to the cell tank 200, the cleaning solution tank 600, the cell detachment enzyme tank 700, the cell culture module 400 and the culture medium module 300 respectively via the pump 500, the culture medium sensor 314 and the pump 320 to control the pump 500, the pump 320, the regulator 330 and the culture medium sensor 314.
- the cell culture system 1000 of the present example may further include a regulator 900 installed onto the cell culture module 400, for regulating the substances in the cell culture module 400 when necessary.
- the cells to be cultured in the cell tank 200 are sent to the cell culture module 400A using the pump 500 to inoculated the cells to be cultured on the sheet-shaped carrier member 14 in the folded state.
- the sheet-shaped carrier member 14 of the cell culture module 400A are in the open state, each pipeline of the system is first configured and then the cells are inoculated on the sheet-shaped carrier member 14 in the open state. Then, the sheet-shaped carrier member 14 of the cell culture module 400A is rendered into the folded state for subsequent cell culture steps, but the disclosure is not limited to the above.
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- Analytical Chemistry (AREA)
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- Apparatus Associated With Microorganisms And Enzymes (AREA)
Description
- The disclosure relates to a culture module, a culture system and a culture method and more particularly, to a cell culture module, a cell culture system and a cell culture method.
- Current carrier scaffolds for cell mass production may be divided into two categories, one being natural materials such as collagen, chitosan, gelatin or the like and the other being synthetic materials such as polycaprolactone (PCL), polystyrene (PS), polypropylene (PP), poly(lactic-co-glycolic acid) (PLGA) or the like. The natural materials are mostly materials derived from animal sources. Although the materials derived from animal sources have lower cytotoxicity and higher biocompatibility, they may carry undetectable animal contaminants. Therefore, the current trend is toward reducing or even eliminating the use of the materials derived from animal sources to reduce the risk of contamination.
- In addition, among current commercially available cell carriers, all the synthetic materials except for alginate-based related products are difficult to degrade, thus causing challenges in collecting the cells. Since the alginate-based related products require a high concentration of calcium ions during cell culture, the cells may be damaged or a tendency to differentiation may be induced in some certain cells (e.g., mesenchymal stem cells). In addition, during degradation of alginate, it is necessary to use a calcium ion chelator and improper usage thereof is very likely to cause damage to the cells. In addition, there is still room for improvement in key techniques for cell collection carrier scaffolds. Thus, current cell mass production technology still remains at a conventional two-dimensional flat plate culture method and the process cannot be adapted to larger scale production.
- Therefore, to find a carrier material suitable for rapid and mass growth of cells and yet devoid of animal contaminants and to enhance cell recovery rate and cell quality are both issues that researchers are eager to solve.
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US 2017/166859 A1 discloses a cell culture carrier module, a bioreactor and a cell recovery method. The cell culture carrier module includes at least one cell culture carrier capable of transforming between a two dimensional structure and a three dimensional structure. The cell culture carrier exhibits the two dimensional structure in a loosened state and exhibits the three dimensional structure in a compressed state. -
US 6 245 557 B1 discloses a cell culture assembly including a housing having a first end and a second end and the side wall disposed between the first and second ends. The side wall and the second end define a cell growth chamber and the first end defines an opening for receiving media and starter culture. The assembly includes a continuous elongated ribbon having a leader at one end and a cell growth portion formed into turns and disposed within the chamber. The first end of the ribbon is threaded through an aperture in the side wall with the leader exposed on the outside of the housing. A sealing member is disposed over the leader and the aperture to hermetically seal the aperture. The sealing member is removable to access the leader to pull the ribbon through the aperture. - The present invention is provided by appended claim 1. The following disclosure serves a better understanding of the present invention. Accordingly, the disclosure provides a culture module, a culture system and a culture method to solve the issues about low cell recovery rate and poor cell quality.
- A cell culture module according to the disclosure includes a casing, a first fixer, a second fixer and a sheet-shaped carrier member. The casing has a chamber and at least one inlet/outlet. The inlet/outlet communicates with the chamber. The casing is a six-sided box-shaped shape. The first fixer is fixed to the casing and located in the chamber. The second fixer is disposed in the chamber and is movable relative to the first fixer. The sheet-shaped carrier member is formed by arranging a plurality of cell culture carriers having straight strip shape and in linear arrangement. Two opposite ends of the sheet-shaped carrier member are respectively fixed to the first fixer and the second fixer. The sheet-shaped carrier member is in an open state or a folded state according to a variation in a distance between the first fixer and the second fixer due to a movement of the second fixer.
- According to the disclosure, a cell culture system includes a cell tank, a culture medium module and a cell culture module. The cell tank and the culture medium module respectively communicate with the cell culture module and the cell culture module includes a casing, a first fixer, a second fixer and a sheet-shaped carrier member. The casing has a chamber and at least one inlet/outlet. The inlet/outlet communicates with the chamber. The first fixer is fixed to the casing and located in the chamber. The second fixer is disposed in the chamber and is movable relative to the first fixer. The sheet-shaped carrier member is formed by arranging a plurality of cell culture carriers and two opposite ends of the sheet-shaped carrier member are respectively fixed to the first fixer and the second fixer. The sheet-shaped carrier member is in an open state or a folded state according to a variation in a distance between the first fixer and the second fixer due to a movement of the second fixer.
- According to the disclosure, a cell culture method adopts the above cell culture module and includes the following steps. Cell are attached on the sheet-shaped carrier member in the folded state. A culture medium is perfused and circulated in the cell culture module and a cell culture is started. The culture medium is discharged and a cleaning solution is perfused and then the remaining culture medium is removed by immersion and cleaning. A cell detachment enzyme is perfused. When the sheet-shaped carrier member is in the open state, the cells are desorbed from the sheet-shaped carrier member and suspended in the suspension of the cell culture module. Moreover, the suspension containing the cells is collected.
- Based on the above, in the cell culture module, the cell culture system and the cell culture method according to the disclosure, by the second fixer, the cell culture carrier may be controlled to switch between the untwisted and twisted state or the open and folded state and cell recovery rate and cell quality may thus be enhanced.
- Several exemplary embodiments accompanied with figures are described in detail below to further describe the disclosure in details.
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FIG. 1A and FIG. 1B are schematic views of a cell culture carrier of a cell culture module, in a twisted state and an untwisted state, respectively, according to an example not part of the present invention. -
FIG. 2A and FIG. 2B are schematic views of a cell culture carrier of a cell culture module, in an untwisted state and a twisted state, respectively, according to another example not part of the present invention. -
FIG. 3 is a schematic view of a cell culture module according to still another example not part of the present invention. -
FIG. 4A and FIG. 4B are schematic views of a cell culture carrier of a cell culture module, in a twisted state and an untwisted state, respectively, according to yet still example not part of the present invention. -
FIG. 5 is a schematic view of a cell culture module according to further still another example not part of the present invention. -
FIG. 6 is a schematic view of a cell culture module according to another example not part of the present invention. -
FIG. 7 is a schematic view of a cell culture module according to still another example not part of the present invention. -
FIG. 8A to FIG. 8F are schematic views illustrating several stages of a cell culture performed by a cell culture system according to an example not part of the present invention. -
FIG. 9 is a flowchart of a cell culture method that may be performed by a cell culture system and a cell culture module according to an exemplary embodiment. -
FIG. 10A and FIG. 10B are respectively schematic views of a sheet-shaped carrier member of a cell culture module in an open state and a folded state according to an exemplary embodiment. -
FIG. 11 is a schematic view of a cell culture module according to another exemplary embodiment. -
FIG. 12A and FIG. 12B are respectively schematic views of a sheet-shaped carrier member of a cell culture module in an open state and a folded state according to another exemplary embodiment. -
FIG. 13 is a schematic view of a cell culture module according to still another exemplary embodiment. -
FIG. 14 is a schematic view of a cell culture module according to yet another exemplary embodiment. -
FIG. 15 is a schematic view of a cell culture module according to an exemplary embodiment. -
FIG. 16 is a schematic view of a cell culture module according to another exemplary embodiment. -
FIG. 17 is a schematic view of a cell culture system according to an exemplary embodiment. - The disclosure is more comprehensively described with reference to the figures of the present embodiments. However, the disclosure may also be implemented in various different forms and is not limited to the embodiments in the present specification. The same or similar reference numerals in the figures represent the same or similar elements and are not repeated in the following paragraphs.
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FIG. 1A and FIG. 1B are respectively schematic views of cell culture carriers of a cell culture module in a twisted state and an untwisted state according to an example not part of the present invention. Referring toFIG. 1A and FIG. 1B , acell culture module 100A of the present example includes areactor 110, afirst fixer 120, asecond fixer 130A and a plurality ofcell culture carriers 140. Thereactor 110 has a chamber C10 and at least one inlet/outlet T12. The chamber C10 is configured to provide space for culturing cells. The inlet/outlet T12 communicates with the chamber C10. Thefirst fixer 120 is fixed to thereactor 110 and located in the chamber C10. Thesecond fixer 130A is disposed in the chamber C10 and is movable relative to thefirst fixer 120. Two ends of thecell culture carriers 140 are respectively fixed to thefirst fixer 120 and thesecond fixer 130A. Thecell culture carriers 140 are in the twisted state as shown inFIG. 1A , or thecell culture carriers 140 are in the untwisted state as shown inFIG. 1B according to a variation in a distance between thefirst fixer 120 and thesecond fixer 130A due to a movement of thesecond fixer 130A. - In other words, when the distance between the
first fixer 120 and thesecond fixer 130A becomes less than a stretch length of thecell culture carriers 140 due to the movement of thesecond fixer 130A, thecell culture carriers 140 are in the twisted state, as shown inFIG. 1A . Thecell culture carriers 140 may have a strip shape. The strip-shapedcell culture carriers 140 may be used in limited space to obtain more area for cells to adhere to so as to increase the number of culturable cells. - In addition, when the distance between the
first fixer 120 and thesecond fixer 130A becomes roughly equal to the stretch length of thecell culture carriers 140 due to the movement of thesecond fixer 130A, thecell culture carriers 140 are rendered in the untwisted state, as shown inFIG. 1B . In this state, the cells may be detached from thecell culture carriers 140 during a change of state of thecell culture carriers 140 from the twisted state to the untwisted state by the action of a substance such as an enzyme which may detach the cells from thecell culture carriers 140. Further, since the distance between thecell culture carriers 140 is increased, an enzyme or the like may act on cells inside thecell culture carriers 140 which are previously difficult to be acted upon by the enzyme, which conduces to enhancement of a cell recovery rate. - In the present example, since the
second fixer 130A is movably disposed in the chamber C10, when thereactor 110 is placed in the state ofFIG. 1A , thesecond fixer 130A moves downward to a position close to thefirst fixer 120 due to its own gravity. To change thecell culture carriers 140 to the untwisted state, thereactor 110 may be placed upside down as shown inFIG. 1B and changed to a state opposite the state inFIG. 1A . In this way, thesecond fixer 130A moves downward to a position away from thefirst fixer 120 due to its own gravity, and thecell culture carriers 140 are stretched by thefirst fixer 120 and thesecond fixer 130A and changed to the untwisted state. In addition, to improve mobility of thesecond fixer 130A, a weight block may be installed onto thesecond fixer 130A to ensure that thesecond fixer 130A may move by its own gravity. - From another point of view, when the
cell culture carriers 140 are in the untwisted state, each of thecell culture carriers 140 is equivalent to a two-dimensional structure. When thecell culture carriers 140 are in the twisted state, the interleavedcell culture carriers 140 are equivalent to a three-dimensional structure. InFIG. 1A , each of thecell culture carriers 140 in the twisted state has a regular spiral shape. However, thecell culture carrier 140 may also be randomly twisted, and thus a plurality ofcell culture carriers 140 in the twisted state may have a coiling shape. However, the disclosure is not limited thereto. InFIG. 1B , each of thecell culture carriers 140 in the untwisted state has a straight strip shape, and thus a plurality ofcell culture carriers 140 in the untwisted state may be arranged in an array of parallel lines. However, thecell culture carriers 140 in the untwisted state may not be parallel to one another, or some of thecell culture carriers 140 may be slightly bent. However, the disclosure is not limited thereto. - A material of the
cell culture carriers 140 includes, for example, polyester (PET), nylon, polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC), polystyrene (PS), polycarbonate (PC), ethylene vinyl acetate (EVA), polyurethane (PU) or the like. However, the disclosure is not limited thereto, and any material having fiber drawing properties may be used as the material for the cell culture carrier of the disclosure. In addition, each of thecell culture carriers 140 may be in the shape of a striped sheet, a threadlike sheet, or in any other suitable shape. - The
cell culture carriers 140 may be a material to which cells may adhere or a material having cell adhesion properties after processing. The above processing methods include surface modification, surface coating, surface microstructurization or the like. Surface modification is achieved by, for example, performing plasma modification on a surface of the material to which cells may adhere, or a surface of a material to which cells cannot adhere to impart the cell adhesion properties to the surface, thereby facilitating adhesion of the cells. Surface coating includes coating, for example but not limited to, collagen, chitosan, gelatin, alginate or the like, onto the surface of the material to which cells may adhere or the surface of the material to which cells cannot adhere, thereby facilitating adhesion of the cells. Surface microstructurization is achieved by, for example, performing laser cutting on the surface of the material to which cells may adhere or the surface of the material to which cells cannot adhere so as to form microchannels, thereby facilitating adhesion of the cells. However, the processing methods of the disclosure are not limited thereto, and any processing method capable of enhancing cell adhesion properties may be applied in the disclosure. - A material of the
reactor 110, thefirst fixer 120 and thesecond fixer 130A includes, for example, polyester (PET), nylon, polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC), polystyrene (PS), ethylene vinyl acetate (EVA), polyurethane (PU), polycarbonate (PC), glass or the like. However, the disclosure is not limited thereto. - In one example not part of the present invention, the inlet/outlet T12 of the
cell culture module 100A may be disposed on one end portion of thereactor 110. When only one single inlet/outlet T12 is disposed in thecell culture module 100A, the inlet/outlet T12 may be used both for entry and exit of a liquid such as a culture medium and a buffer solution and for cell collection. However, in other examples, the entry and exit of the culture medium and the buffer solution and the cell collection may respectively use different channels, in view of preventing the whole module from contamination. In detail, thecell culture module 100A of the present example may include a plurality of inlets/outlets T12, T14, T16, T18 (not illustrated), T21 and T23, wherein the inlet/outlet T12 is disposed on one end portion of thereactor 110 and enables the cell collection. The inlets/outlets T14, T16 and T18 may be disposed on a side surface of thereactor 110 and close to the end portion of thereactor 110 on which the inlet/outlet T12 is disposed, so as to allow entry of different buffer solutions and culture media into thereactor 110. It should be noted that the numbers of the inlets/outlets T14, T16 and T18 may vary depending on the type and requirements of the actually injected liquid, and are not limited to those mentioned herein. The inlets/outlets T21 and T23 are disposed on the other end portion of thereactor 110, opposite the inlet/outlet T12. The inlet/outlet T21 allows the entry and exit of liquid such as a culture medium or a buffer solution, and the inlet/outlet T23 is a reserved hole, wherein the design in which the inlet/outlet T21 is located opposite the inlets/outlets T14, T16 and T18 facilitates distribution and circulation of liquid within the chamber C10. - The
cell culture module 100A of the present example may further include aturbulent part 150 disposed in the chamber C10 and between the inlet/outlet T12 and thefirst fixer 120. To be specific, theturbulent part 150 may be arranged at the same plane height as the inlets/outlets T14, T16 and T18. The liquid that enters via the inlets/outlets T14, T16 and T18, after being rotated by theturbulent part 150, may drive circulation of the liquid in the chamber C10. As a result, substances in the liquid in the chamber C10 may be uniformly distributed. - The cell culture module may have different designs depending on whether it is reusable. When the cell culture module is reusable, as shown in the present example, the
reactor 110 of thecell culture module 100A further includes abody 112 and acover 114, thebody 112 and thecover 114 being connected with each other to form the chamber C10. By opening thecover 114, the communication with the chamber C10 becomes possible so that thecell culture carriers 140 may be replaced. In addition, a sealingpart 116 may further be disposed between thebody 112 and thecover 114 to maintain sealability of the chamber C10. When the cell culture module is for one time use only, thereactor 110 is integrally formed. -
FIG. 2A and FIG. 2B are schematic views of a cell culture carrier of a cell culture module, in the untwisted state and the twisted state, respectively, according to another example not part of the present invention. Referring toFIG. 2A and FIG. 2B , acell culture module 100B of the present example is similar to thecell culture module 100A ofFIG. 1A . Nonetheless, it should be noted that thecell culture module 100B of the present example further includes amagnetic control part 160A. Correspondingly, asecond fixer 130B of the present example has magnetism. Accordingly, themagnetic control part 160A may control thesecond fixer 130B to move, using magnetic force such as magnetic attractive force or magnetic repulsive force. As shown inFIG. 2A , when themagnetic control part 160A magnetically controls thesecond fixer 130B to move to a position away from thefirst fixer 120, thecell culture carriers 140 are rendered in the untwisted state. As shown inFIG. 2B , when themagnetic control part 160A controls thesecond fixer 130B to move to a position close to thefirst fixer 120, thecell culture carriers 140 are rendered in the twisted state. The shape of themagnetic control part 160A of the present example roughly matches the shape of thereactor 110. Moreover, themagnetic control part 160A itself is movable, thereby driving thesecond fixer 130B to move. However, the disclosure is not limited thereto. -
FIG. 3 is a schematic view of a cell culture module according to still another example not part of the present invention. Referring toFIG. 3 , acell culture module 100C of the present example is similar to thecell culture module 100B ofFIG. 2A . Nonetheless, it should be noted that, when amagnetic control part 160B of the present example intends to control thesecond fixer 130B to move, themagnetic control part 160B directly moves to one side of thereactor 110 away from thefirst fixer 120 and then uses magnetic force to attract thesecond fixer 130B to move to a position away from thefirst fixer 120. By contrast, after themagnetic control part 160B is removed, thesecond fixer 130B will move to a position close to thefirst fixer 120 due to its own gravity. -
FIG. 4A and FIG. 4B are schematic views of a cell culture carrier of a cell culture module, in the twisted state and the untwisted state, respectively, according to yet still another example not part of the present invention. Referring toFIG. 4A and FIG. 4B , acell culture module 100D of the present example is similar to thecell culture module 100A ofFIG. 1A . Nonetheless, it should be noted that thecell culture module 100D of the present example further includes afastener 170. In addition, areactor 110A further includes an elastic corrugated structure 110A1. When no force is applied thereto, the elastic corrugated structure 110A1 is, for example, in a stretched state as shown inFIG. 4B . Thefastener 170 is configured to control the elastic corrugated structure 110A1 to remain in a compressed state or not, so that the elastic corrugated structure 110A1 may switch between the stretched state as shown inFIG. 4B and the compressed state as shown inFIG. 4A . Asecond fixer 130C of the present example is fixed to thereactor 110A, and the elastic corrugated structure 110A1 is located between thefirst fixer 120 and thesecond fixer 130C. When thefastener 170 is fastened, the elastic corrugated structure 110A1 is in the compressed state. Thus, thefirst fixer 120 and thesecond fixer 130C approach each other to render thecell culture carriers 140 in the twisted state. When thefastener 170 is released, the elastic corrugated structure 110A1 is in the stretched state. Thus, thefirst fixer 120 and thesecond fixer 130C are away from each other to render thecell culture carriers 140 in the untwisted state. It should be noted that although thefastener 170 is taken as an example in the present example, thefastener 170 may also be arbitrarily replaced with other fixers, such as a velcro, a screw, a rope and the like. -
FIG. 5 is a schematic view of a cell culture module according to further still another example not part of the present invention. Referring toFIG. 5 , acell culture module 100E of the present example is similar to thecell culture module 100A ofFIG. 1A . Nonetheless, it should be noted that thecell culture module 100E of the present example further includes arod 180 and aguide hole 182. Theguide hole 182 is disposed on one end of areactor 110B, opposite thefirst fixer 120, so as to guide therod 180 to be movably inserted through thereactor 110B. Therod 180 is connected to thesecond fixer 130A and configured to control thesecond fixer 130A to move. By controlling the extent to which therod 180 is inserted into thereactor 110B, it is possible to control thesecond fixer 130A to move to a position close to or away from thefirst fixer 120. -
FIG. 6 is a schematic view of a cell culture module according to another example not part of the present invention. Referring toFIG. 6 , acell culture module 100F of the present example is similar to thecell culture module 100A ofFIG. 1A . Nonetheless, it should be noted that thecell culture module 100F of the present example further includes a fluidpressure control part 190 disposed in thereactor 110 and inside the chamber C10. Thesecond fixer 130A is located between the fluidpressure control part 190 and thefirst fixer 120. The fluidpressure control part 190 is configured to control thesecond fixer 130A to move. For example, the fluidpressure control part 190 is applicable to bags for containing fluids. However, the disclosure is not limited thereto. As a gas, water, oil or other fluid contained in the fluidpressure control part 190 increases, the volume of the fluidpressure control part 190 also increases, thus pushing thesecond fixer 130A to move in a direction approaching thefirst fixer 120. As the gas, water, oil or other fluid contained in the fluidpressure control part 190 decreases, the volume of the fluidpressure control part 190 also decreases, thus allowing thesecond fixer 130A to move in a direction away from thefirst fixer 120. -
FIG. 7 is a schematic view of a cell culture module according to still example not part of the present invention. Referring toFIG. 7 , acell culture module 100G of the present example is similar to thecell culture module 100A ofFIG. 1A . Nonetheless, it should be noted that, in thecell culture module 100G of the present example, asecond fixer 130D is screwed onto a wall of areactor 110C. In other words, screw threads matching each other are provided on contact surfaces of both thesecond fixer 130D and thereactor 110C. Accordingly, when thesecond fixer 130D is rotated relative to thereactor 110C, thesecond fixer 130D approaches or departs from thefirst fixer 120. A knob 130D1 is further provided on thesecond fixer 130D of the present example to enable a user to easily apply force to rotate thesecond fixer 130D. -
FIG. 8A to FIG. 8F are schematic views illustrating several stages of a cell culture performed by a cell culture system according to an example not part of the present invention. Referring first toFIG. 8A , acell culture system 1000 of the present example includes acell tank 200, aculture medium module 300 and acell culture module 400. Thecell tank 200 and theculture medium module 300 respectively communicate with thecell culture module 400. Thecell culture module 400 may be any cell culture module of the aforesaid examples or any other cell culture module complying with the spirit of the disclosure. The details of thecell culture module 400 are omitted herein. Since thecell culture system 1000 of the present example uses thecell culture module 400 that is the same as the cell culture module of the aforesaid examples, thecell culture system 1000 of the present example may enhance the yield and the recovery rate of cell culture. In addition, thecell culture system 1000 of the present example may optionally further include apump 500, acleaning solution tank 600 and a celldetachment enzyme tank 700. Thecell tank 200 and theculture medium module 300 respectively communicate with thecell culture module 400 via thepump 500. Both thecleaning solution tank 600 and the celldetachment enzyme tank 700 also communicate with thecell culture module 400 via, for example, thepump 500. - In the present example, the
cell tank 200, theculture medium module 300, thecleaning solution tank 600 and the celldetachment enzyme tank 700 all communicate with thecell culture module 400 via thepump 500. Thecell tank 200 is connected to thepump 500 by which thecell tank 200 is connected to the inlet/outlet T12 of thecell culture module 400. Thecleaning solution tank 600 is connected to thepump 500 by which thecleaning solution tank 600 is connected to the inlet/outlet T14 of thecell culture module 400. The celldetachment enzyme tank 700 is connected to thepump 500 by which the celldetachment enzyme tank 700 is connected to the inlet/outlet T16 of thecell culture module 400. Theculture medium module 300 is connected to thepump 500 by which theculture medium module 300 is connected to the inlet/outlet T18 of thecell culture module 400. The culture medium of theculture medium module 300 enters thecell culture module 400 via the inlet/outlet T18, and then flows back from thecell culture module 400 to theculture medium module 300 via the inlet/outlet T21 on the other end. Therefore, the culture medium of theculture medium module 300 may be recycled for use. To monitor quality of the culture medium of theculture medium module 300, aculture medium tank 310 of theculture medium module 300 is equipped with aculture medium sensor 314. Theculture medium sensor 314 is, for example, a pH meter, a thermometer, or a dissolved oxygen meter. In addition, a stirringbar 312 is further disposed in theculture medium tank 310 to maintain uniform distribution of culture substances in the culture medium. In addition, theculture medium module 300 is further equipped with apump 320 and aregulator 330. When theculture medium sensor 314 senses that the quality of the culture medium in theculture medium tank 310 is lower than a threshold value, thepump 320 extracts regulating substances from theregulator 330 into theculture medium tank 310 so as to improve the quality of the culture medium. Acell culture system 1000 of the present example may further include acontroller 800. Thecontroller 800 is connected to thecell tank 200, thecleaning solution tank 600, the celldetachment enzyme tank 700, thecell culture module 400 and theculture medium module 300 respectively via thepump 500, theculture medium sensor 314 and thepump 320 to control thepump 500, thepump 320, theregulator 330 and theculture medium sensor 314. In addition, thecell culture system 1000 of the present example may further include aregulator 900 installed onto thecell culture module 400, for regulating the substances in thecell culture module 400 when necessary. -
FIG. 9 is a flowchart of a cell culture method that may be performed by a cell culture system and a cell culture module according to examples not being part of the invention and to an exemplary embodiment. Referring toFIG. 8A andFIG. 9 , during a cell culture process, first of all, thecell culture carrier 140 of thecell culture module 400 is rendered in the twisted state, and arrangement of pipelines of the system is completed (step S110). As mentioned in the aforesaid configurations, a method of rendering thecell culture carrier 140 of thecell culture module 400 in the twisted state includes causing thesecond fixer 130A to move to a position close to thefirst fixer 120. However, the way of performing the method is not limited. As in the aforesaid configurations, thesecond fixer 130A may be displaced through gravity, magnetic force, or other mechanical force. In the present example, the movement of thesecond fixer 130A may be controlled with the assistance of the magnetic control part 160A., but is not limited thereto. - Referring to
FIG. 8A andFIG. 9 , next, cells in thecell tank 200 which are to be cultured are sent to thecell culture module 400 using thepump 500, so as to inoculate the cells to be cultured onto thecell culture carrier 140 in the twisted state (step S120). The cells to be cultured are, for example but not limited to, stem cells or differentiated cells. Specifically, the cells to be cultured are, for example but not limited to, African green monkey kidney cell line (Vero), human adipose-derived stem cells (ADSCs), mesenchymal stem cells (MSCs), Madin-Darby Canine Kidney (MDCK) cells, human embryonic kidney cells 293 (HEK 293 cells) or the like. In the present alternative, a culture medium is first added to thecell culture carrier 140, and the cells are then inoculated to thecell culture carrier 140. In another exemplary alterantive, a cell culture medium containing the cells may be uniformly added directly to thecell culture carrier 140. The culture medium is a standard growth culture medium commonly used for cell culture, and examples thereof include a culture medium having fetal bovine serum (FBS) or a serum-free medium. However, the disclosure is not limited thereto. In addition, it should be understood that, depending on different cell properties, requirements of operating concentration of the cell culture medium is different. Hence, the operating concentration may be adjusted according to cell properties, and growth factors, antibiotics or the like may be added to the culture medium if needed. The cells are caused to adhere to the cell culture carrier. In the present configuration, thecell culture carrier 140 is placed in thecell culture module 400 under specific growth conditions (e.g., specific temperature, humidity, or carbon dioxide concentration) such that the cells adhere to thecell culture carrier 140. - In other exemplary alternatives, each pipeline of the system may also be configured first when the
cell culture carriers 140 are in the untwisted state and then thecell culture carriers 140 in the untwisted state are inoculated. When the cells are attached, the twisting action of thecell culture carriers 140 is performed, but the disclosure is not limited to the above. - Referring to
FIG. 8B andFIG. 9 , next, after the cell adhesion, a culture medium is perfused and circulated to start the cell culture (step S130). That is, after the aforesaid steps are completed, thepump 500 may be turned on to allow the culture medium of theculture medium module 300 to flow into thecell culture module 400, and the culture medium is continuously circulated between theculture medium module 300 and thecell culture module 400 so as to culture the cells. The cell culture is performed by, for example, static culture or dynamic culture. The dynamic culture may be performed by disturbing the culture medium surrounding the cell culture carrier. A method of disturbing the culture medium includes, for example, using theturbulent part 150 as inFIG. 1A , which is not illustrated in the present configuration. In one exemplary example, the number of cells after culture may increase to 100 times or more the original number of cells. In another alternative, the number of cells after culture may increase to 2000 times or more the original number of cells. - It is noting that since different cells have different properties, the cell culture conditions may be adjusted based on different cell types. For example, when culturing mammalian cells, the cells may be cultured at conditions of 37°C and 5% of COz, and the pH value of the culture medium is maintained within a physiological range thereof. For example, for most animal cells, a suitable pH value of the culture medium is 7.2 to 7.4.
- Referring to
FIG. 8C andFIG. 9 , next, the culture medium is discharged and a cleaning solution is perfused, and the remaining culture medium is removed by immersion and cleaning in the cleaning solution (step S140). That is, all of the culture medium in thecell culture module 400 is sent back to theculture medium module 300. Then, the cleaning solution in thecleaning solution tank 600 is caused to flow into thecell culture module 400 by thepump 500, and the remaining culture medium is removed by immersion and cleaning in the cleaning solution. The cleaning solution is, for example, a phosphate buffered saline solution. - Referring to
FIG. 8D andFIG. 9 , next, a cell detachment enzyme is perfused to immerse the cell culture carrier and the cells therein (step S150). That is, all of the cleaning solution in thecell culture module 400 is sent back to thecleaning solution tank 600. Then, the cell detachment enzyme in the celldetachment enzyme tank 700 is caused to flow into thecell culture module 400 by thepump 500, and thecell culture carrier 140 in the twisted state and the cells are immersed in the cell detachment enzyme. The cell detachment enzyme is, for example, trypsin, tryp LE, accutase, accumax, or collagenase. However, the disclosure is not limited thereto, and other enzymes or reagents capable of cell detachment may also be used. - Referring to
FIG. 8E andFIG. 9 , next, the cell culture carrier is loosened and transformed into a two-dimensional structure, causing detachment of the cells (step S160). That is, thecell culture carrier 140 of thecell culture module 400 is changed from the twisted state to the untwisted state. As mentioned in the aforesaid alternatives, a method of rendering thecell culture carrier 140 of thecell culture module 400 in the untwisted state includes causing thesecond fixer 130A to move to a position away from thefirst fixer 120. In the present configuration, the movement may be performed with the assistance of themagnetic control part 160A. - Referring to
FIG. 8F andFIG. 9 , next, a cell suspension is collected (step S170). That is, a cell suspension in thecell culture module 400 is sent to thecell tank 200 through thepump 500. Since the cell recovery is performed when thecell culture carrier 140 is in the untwisted state, the loosened structure allows thecell culture carrier 140 to sufficiently react with a reagent containing the cell detachment enzyme, and the loosened structure also facilitates the detachment of the cells on an inner layer of thecell culture carrier 140, thereby enhancing the cell recovery rate. - It should be noted that, in the aforesaid alternatives, the
cell culture carrier 140 is loosened after the cell detachment enzyme is perfused, and the cells are then collected. However, in other exemplary alternatives, thecell culture carrier 140 may first be loosened to return to the two-dimensional state. The cell detachment enzyme is then perfused to collect the cultured cells. The disclosure is not limited to the above description. - In the above configurations, the reactor of the cell culture is cylindrical, but is not limited thereto. In other configurations, the cell culture module may also be designed with other shapes as desired. It should be noted that in order to match the cell culture modules of different shapes, the cell culture carriers are also adaptable to different laying methods.
-
FIG. 10A and FIG. 10B are respectively schematic views of a sheet-shaped carrier member of a cell culture module in an open state and a folded state according to another exemplary embodiment. Referring toFIG. 10A and FIG. 10B , acell culture module 100H of the present embodiment includes acasing 111, afirst fixer 120, asecond fixer 130 and a sheet-shapedcarrier member 14. Thecasing 111 has a chamber C10 and at least one inlet/outlet T12, wherein the at least one inlet/outlet T12 communicates with the chamber C10. Thefirst fixer 120 is fixed to thecasing 111 and located in the chamber C10. Thesecond fixer 130 is disposed in the chamber C10 and is movable relative to thefirst fixer 120. The sheet-shapedcarrier member 14 is formed by arranging a plurality ofcell culture carriers 140 and two opposite ends of the sheet-shapedcarrier member 14 are respectively fixed to thefirst fixer 120 and thesecond fixer 130. The sheet-shapedcarrier member 14 is in the open state as shown inFIG. 10A , or the sheet-shapedcarrier member 14 is in the folded state as shown inFIG. 10B according to a variation in a distance between thefirst fixer 120 and thesecond fixer 130 due to a movement of thesecond fixer 130. - In the present embodiment, the
casing 111 is a six-sided box-shaped shape, such as a flat plate shape. When a plurality ofcell culture modules 100H are used, a plurality ofcasings 111 may be stacked with each other to more effectively utilize the entire space. Further, thecell culture carriers 140 are designed to be arranged in the sheet-shapedcarrier member 14 with a variation in the shape of thecasing 111, so that the sheet-shapedcarrier member 14 may be covered on one surface of the flat plate-shapedcasing 111 when the sheet-shapedcarrier member 14 is in the open state. - The straight strip
cell culture carriers 140 may specifically be a single-line, double-line, or yarn structure and the line is configured as a straight line, a curve, a spiral curve, a wavy curve, a zigzag curve, an inverted curve, or a sheet curve, etc., but is not limited to the above. The plurality of straight stripcell culture carriers 140 are arranged to form the sheet-shapedcarrier member 14 and thecell culture carriers 140 may be arranged in a parallel arrangement or an interleaved arrangement and the arranged sheet-shapedcarrier member 14 may be single-layered or multi-layered, but the disclosure is not limited thereto. - In the present embodiment, a plurality of
cell culture carriers 140 are arranged in a single layer in parallel to form the sheet-shapedcarrier member 14 and thecell culture carriers 140 are respectively fixed to thefirst fixer 120 and thesecond fixer 130 at two opposite ends of the axial extending direction thereof. Therefore, when the distance between thefirst fixer 120 and thesecond fixer 130A becomes less than a stretch length of the sheet-shaped carrier member 14 (or the cell culture carriers 140) due to the movement of thesecond fixer 130, the sheet-shaped carrier member 14 (or the cell culture carriers 140) is rendered in the folded state as shown inFIG. 10B . In this state, a plurality ofcell culture carriers 140 may be used in limited space to obtain more area for cells to adhere to so as to increase the number of culturable cells. When the distance between thefirst fixer 120 and thesecond fixer 130 becomes roughly equal to the stretch length of the sheet-shaped carrier member 14 (or the cell culture carriers 140) due to the movement of thesecond fixer 130, the sheet-shaped carrier member 14 (or the cell culture carriers 140) is rendered in the open state as shown inFIG. 10A . The cells may be detached from thecell culture carriers 140 during a change of state of the sheet-shapedcarrier member 14 from the folded state to the open state. Further, since the distance between thecell culture carriers 140 is increased, a substance such as an enzyme for facilitating detachment of the cells from thecell culture carriers 140 may be injected, and the substance may easily reach all the cells to sufficiently perform a reaction, which conduces to enhancement of a cell recovery rate. - Please refer to
FIG. 11 . In another exemplary embodiment, a plurality ofcell culture carriers 140 are arranged in a single layer in parallel to form the sheet-shapedcarrier member 14, the sheet-shapedcarrier member 14 further include a first connectingportion 142 and a second connectingportion 144, and thecell culture carriers 140 are respectively fixed to the first connectingportion 142 and the second connectingportion 144 at two opposite ends of the axial extending direction thereof. The first connectingportion 142 and the second connectingportion 144 are adjacently connected to thefirst fixer 120 and thesecond fixer 130. In detail, the first connectingportion 142 and the second connectingportion 144 are two long sides of the sheet-shapedcarrier member 14, and the sides in the sheet-shapedcarrier member 14 fixed to thefirst fixer 120 and thesecond fixer 130 are two short sides in the sheet-shapedcarrier member 14. That is, the first connectingportion 142, the second connectingportion 144, thefirst fixer 120 and thesecond fixer 130 are all located on different sides of the sheet-shapedcarrier member 14. - Further, in the embodiments of
FIG. 1A to FIG. 10B , a moving direction D of the second fixer is roughly parallel to the axial extending direction of thecell culture carriers 140, but in the embodiment ofFIG. 11 , the movement direction D of thesecond fixer 130 is roughly perpendicular to the axial extending direction of thecell culture carriers 140 in the sheet-shapedcarrier member 14. In other exemplary embodiments, the moving direction D of thesecond fixer 130 is roughly at an angle to the axial extending direction of thecell culture carriers 140 in the sheet-shapedcarrier member 14 and is not limited thereto. - Refer to all of
FIG. 11 ,FIG. 12A and FIG. 12B . It is noted that, in order to simplify the illustration, thecell culture carriers 140 are not illustrated inFIG. 12A and FIG. 12B , but it should be understood from the above description that the configuration of thecell culture carriers 140 may include making the axial extending direction of thecell culture carriers 140 perpendicular, angled, or parallel to the moving direction D of thesecond fixer 130. In the embodiment ofFIG. 11 , when the sheet-shapedcarrier member 14 is in the open state, the first connectingportion 142 and the second connectingportion 144 are roughly straight lines or slightly curved, but in the different embodiments ofFIG. 12A and FIG. 12B , the first connectingportion 142 and the second connectingportion 144 may be designed to have a zigzag or wavy shape via molding, but the disclosure is not limited thereto. The uneven shape of the first connectingportion 142 and the second connectingportion 144, such as a zigzag or a wave shape, may guide the sheet-shapedcarrier member 14 to be uniformly folded and compressed when thesecond fixer 130 is moved toward thefirst fixer 120, so that when the sheet-shapedcarrier member 14 is in the folded state, a suitable space exists between the plurality ofcell culture carriers 140 to prevent a portion of the region between the plurality ofcell culture carriers 140 from being too dense due to uneven extrusion, resulting in adverse cell growth. - As shown in
FIG. 12A and FIG. 12B , the sheet-shapedcarrier members 14 in acell culture module 100J further include a third connectingportion 146. The third connectingportion 146 is disposed between the first connectingportion 142 and the second connectingportion 144, such that one end of thecell culture carriers 140 is fixed to the first connectingportion 142 and the other end of thecell culture carriers 140 is extended to the third connectingportion 146 and then extended to thesecond connection 144 via the third connectingportion 146. The third connectingportion 146 not only has the same shaping function as the folding guide of the first connectingportion 142 and the second connectingportion 144, when the distance between the first connectingportion 142 and the second connectingportion 144 is longer, the configuration of the third connectingportion 146 may also provide a fixed support function to prevent thecell culture carriers 140 from sagging due to the excessive distance between the two ends. In particular, the number of the third connectingportion 146 may not be limited to one. - In one exemplary embodiment, the
casing 111 has a taperedportion 113 and at least one inlet/outlet T12 is disposed at the taperedportion 113. The taperedportion 113 is gradually narrowed outward from thecasing 111 to form, for example, a funnel-shaped structure and the taperedportion 113 allows a cell collection fluid to easily flow out during cell collection, thereby reducing cell residue and allowing the gas remaining in the chamber C10 to be easily discharged. Of course, the taperedportion 113 may also effectively collect the fluid entering the chamber C10 to facilitate discharge. - In one exemplary embodiment, when only one single inlet/outlet T12 is disposed in the cell culture module, the inlet/outlet T12 may be used both for entry and exit of a liquid such as a culture medium and a buffer solution and for cell collection. However, in other exemplary embodiments, the entry and exit of the culture medium and the buffer solution and the cell collection may respectively use different channels, in view of preventing the whole module from contamination. In detail, the
cell culture modules 100H to 100J of the present embodiment may include a plurality of inlets/outlets T12, T14, T16 and T18, wherein the inlet/outlet T12 is disposed at the taperedportion 113 and the collection of cells may be performed via the configuration of the inlet/outlet T12. The inlets/outlets T14, T16 and T18 may be disposed at the other side of thecasing 111 opposite to the taperedportion 113 to respectively allow entry of different buffer solutions and culture media. It should be noted that the number of the inlets/outlets T14, T16 and T18 may be varied according to the actual type of liquid injected and is not limited to the above. In particular, the design of the relative positions of the inlet/outlet T12 and the inlets/outlets T14, T16 and T18 facilitates the distribution and flow circulation of the fluid in the chamber C10. Moreover, thecell culture modules cell culture modules casing 111 may be designed as two separable components, that is, thecasing 111 further includes abody 112 and acover 114, or may be further provided with a sealing member 116 (112, 114 and 116 are not shown in the figure, it may refer toFIG. 1A ) and the functions and objects thereof are the same as those described above and are not repeated herein. When thecell culture modules casing 111 is integrally formed and a two-piece design is unnecessary. - In addition, in the embodiments of the
cell culture modules second fixer 130 may be may be displaced through gravity, magnetic force, or other mechanical force, thereby changing the state of the sheet-shapedcarrier member 14. In detail, when gravity is configured to displace thesecond fixer 130, since thesecond fixer 130 is movably disposed in the chamber C10, when thecasing 111 is placed upright, thesecond fixer 130 moves downward to a position close to thefirst fixer 120 due to its own gravity. When the sheet-shapedcarrier member 14 is to be transformed into the open state, thecasing 111 may be raised toward the other corresponding direction, so that thesecond fixer 130 moves downward to a position away from thefirst fixer 120 due to its own gravity and the sheet-shapedcarrier member 14 is stretched by thefirst fixer 120 and thesecond fixer 130 and changed to the open state. In addition, to improve mobility of thesecond fixer 130, a weight block may be attached to thesecond fixer 130 to ensure that thesecond fixer 130 may move by its own gravity. - Referring to
FIG. 13 , in one exemplary embodiment, if thesecond fixer 130 is displaced via magnetic force, then thecell culture module 100K further includes a magnetic control part 160K. In contrast, asecond fixer 130K of the present embodiment has magnetism. Therefore, the magnetic control part 160K may control thesecond fixer 130K to move by a magnetic force such as a magnetic attraction force or a magnetic repulsion force. When the magnetic control part 160K magnetically controls thesecond fixer 130K to move to a position away from thefirst fixer 120, the sheet-shapedcarrier member 14 is in the open state. When the magnetic control part 160K controls thesecond fixer 130K to move to a position close to thefirst fixer 120, the sheet-shapedcarrier member 14 is in the folded state. The shape of the magnetic control part 160K of the present embodiment is not limited as long as the magnetic control part 160K may be close to the surface of thecasing 111 and themagnetic control part 160A itself is movable, thereby driving thesecond fixer 130K to move, but the disclosure is not limited thereto. In another exemplary embodiment, thecell culture module 100K may be placed upright to provide thesecond fixer 130K to assist in moving displacement due to its own weight. - Referring to
FIG. 14 , in one exemplary embodiment, acell culture module 100L further includes afastener 170. In addition, thecasing 111 further has an elasticcorrugated structure 111A. Theelastic crease structure 111A is the same as the elastic corrugated structure 1 10A1 in thecell culture module 100D ofFIG. 4A and FIG. 4B described above. In an unstressed state, the elasticcorrugated structure 111A is, for example, the stretched state ofFIG. 14 . Thefastener 170 is configured to control whether the elasticcorrugated structure 111A maintains a compressed state or not to switch between the stretched state and the compressed state. Asecond fixer 130L of the present embodiment is fixed to thecasing 111 and the elasticcorrugated structure 111A is located between thefirst fixer 120 and thesecond fixer 130L. When thefastener 170 is fastened, the elasticcorrugated structure 111A is in a compressed state and therefore thefirst fixer 120 and thesecond fixer 130L are close to each other, so that the sheet-shapedcarrier member 14 is in the folded state. When thefastener 170 is unfastened, the elasticcorrugated structure 111A is in the stretched state and therefore thefirst fixer 120 and thesecond fixer 130L are away from each other, so that the sheet-shapedcarrier member 14 is in the open state. It should be noted that although thefastener 170 is taken as an example in the present embodiment, thefastener 170 may also be arbitrarily replaced with other fixers, such as a velcro, a screw, a rope and the like. - Referring to
FIG. 15 , in one exemplary embodiment, acell culture module 100M is similar to thecell culture module 100E ofFIG. 5 and further includes arod 180 and aguide hole 182. Theguide hole 182 is located at one end of thecasing 111 opposite to thefirst fixer 120 to guide therod 180 to movably penetrate thecasing 111. Therod 180 is connected to thesecond fixer 130 to control thesecond fixer 130 to move. By controlling the degree of stretch of therod 180 into thecasing 111, thesecond fixer 130B may be controlled to move to a position close to or away from thefirst fixer 120. It should be noted that in the present embodiment, thesecond fixer 130 and the taperedportion 113 are located at corresponding different sides of thecasing 111, but in other exemplary embodiments, thesecond fixer 130 and the taperedportion 113 may be at the same side of the casing 111 (i.e., therod 180 and theguide hole 182 are disposed at the same side as the tapered portion 113), but the disclosure is not limited thereto. - Referring to
FIG. 16 , in one exemplary embodiment, acell culture module 100N is similar to thecell culture module 100F ofFIG. 6 and further includes a fluidpressure control part 190 disposed at thecasing 111 and located in the chamber C10. Thesecond fixer 130 is located between the fluidpressure control part 190 and thefirst fixer 120. The fluidpressure control part 190 is configured to control thesecond fixer 130 to move. For example, the fluidpressure control part 190 is applicable to bags for containing fluids. However, the disclosure is not limited thereto. As a gas, water, oil or other fluid contained in the fluidpressure control part 190 increases, the volume of the fluidpressure control part 190 also increases, thus pushing thesecond fixer 130 to move in a direction approaching thefirst fixer 120. As the gas, water, oil or other fluid contained in the fluidpressure control part 190 decreases, the volume of the fluidpressure control part 190 also decreases, thus allowing thesecond fixer 130 to move in a direction away from thefirst fixer 120. In the present embodiment, thesecond fixer 130 and the taperedportion 113 are located at corresponding different sides of thecasing 111, but in other exemplary embodiments, thesecond fixer 130 and the taperedportion 113 may be at the same side of the casing (i.e., the fluidpressure control part 190 is disposed at the same side as the tapered portion 113), but the disclosure is not limited thereto. -
FIG. 17 is a schematic of a cell culture system according to another exemplary embodiment. A cell culture system 2000 of the present embodiment includes acell tank 200, aculture medium module 300 and acell culture module 400A. Thecell tank 200 and theculture medium module 300 respectively communicate with thecell culture module 400A. Thecell culture module 400A may be the cell culture module of each of the foregoing embodiments (such as thecell culture modules 100H to 100N) or other cell culture modules conforming to the spirit according to one or more exemplary embodiments and a detailed description of thecell culture module 400A is omitted herein. Since a cell culture system 2000 of the present embodiment adopts the samecell culture module 400A as the cell culture module of each of the foregoing embodiments, the cell culture system 2000 of the present embodiment may increase the yield and recovery rate of the cell culture. In addition, the cell culture system 2000 of the present embodiment may optionally further include apump 500, acleaning solution tank 600, a celldetachment enzyme tank 700 and acontroller 800. Thecell tank 200 and theculture medium module 300 respectively communicate with thecell culture module 400A via thepump 500. Thecleaning solution tank 600 and the celldetachment enzyme tank 700 also both communicate with thecell culture module 400A, such as communicate with thecell culture module 400A via thepump 500. Thecontroller 800 is connected to thecell tank 200, thecleaning solution tank 600, the celldetachment enzyme tank 700, thecell culture module 400A and theculture medium module 300 respectively via thepump 500, theculture medium sensor 314 and thepump 320 to control thepump 500, thepump 320, theregulator 330 and theculture medium sensor 314. - When performing cell culture, first, the cells to be cultured are attached to the sheet-shaped
carrier member 14 in the folded state. In detail, the sheet-shapedcarrier member 14 of thecell culture module 400A may be first in the folded state and the configuration of each pipeline of the system may be completed. In particular, the method of configuration of the sheet-shapedcarrier member 14 of thecell culture module 400A in the folded state includes moving thesecond fixer 130 to a position close to thefirst fixer 120. However, the method is not limited thereto and as in the foregoing embodiments, thesecond fixer 130 may be displaced by gravity, magnetic force, or other mechanical force, which is not repeated herein. Next, the cells to be cultured in thecell tank 200 are sent to thecell culture module 400A using thepump 500 to inoculated the cells to be cultured on the sheet-shapedcarrier member 14 in the folded state. In other exemplary embodiments, when the sheet-shapedcarrier member 14 of thecell culture module 400A are in the open state, each pipeline of the system is first configured and then the cells are inoculated on the sheet-shapedcarrier member 14 in the open state. Then, the sheet-shapedcarrier member 14 of thecell culture module 400A is rendered into the folded state for subsequent cell culture steps, but the disclosure is not limited to the above. - After the cells are attached, a culture medium is perfused and circulated in the
cell culture module 400A and a cell culture is started. Next, the culture medium is discharged and a cleaning solution is perfused and then the remaining culture medium is removed by immersion and cleaning. - Next, a cell detachment enzyme is perfused such that the sheet-shaped
carrier member 14 and the cells are immersed therein and when the sheet-shapedcarrier member 14 is in the open state, the cells are desorbed from the sheet-shapedcarrier member 14 and suspended in the suspension of thecell culture module 400A. In detail, in one exemplary embodiment, the cell desorbing enzyme may be perfused first and then the sheet-shapedcarrier member 14 is loosened from the folded state and transformed into the open state of a two-dimensional structure. In other exemplary embodiments, the sheet-shapedcarrier member 14 may also first be loosened from the folded state and transformed into the open state of a two-dimensional structure and then the cell detachment enzyme is perfused, but the disclosure is not limited to the above. - Lastly, the suspension containing the cells is collected. The detailed operation steps are the same as those of the foregoing
cell culture system 1000 and are not repeated herein. - As mentioned above, in the cell culture module and cell culture system in the present embodiment, since the second fixer is movable, the sheet-shaped carrier member may switch between the open state and the folded state according to a variation in a distance between the first fixer and the second fixer at two ends of the sheet-shaped carrier member. The sheet-shaped carrier member in the folded state helps to increase the yield of the cell culture, and the sheet-shaped carrier member in the open state may improve the cell recovery rate and the quality of the collected cells.
- It should be noted that in the disclosure, when the cell culture carriers are in the untwisted/twisted state and the sheet-shaped carrier member is in the open/folded state, the cell growth region created by the plurality of cell culture carriers is roughly changed between a two-dimensional surface state/three-dimensional space, which is intended to be described in terms of the different laying methods of the cell culture carriers, but the disclosure is not limited thereto.
-
- 100A-100N: cell culture module
- 110, 110A, 110B, 110C: reactor
- 110A1, 111A: elastic corrugated structure
- 111: casing
- 112: body
- 113: tapered portion
- 114: cover
- 116: sealing member
- 120: first fixer
- 130, 130A, 130B, 130C, 130D, 130K, 130L: second fixer
- 130D1: knob
- 14: sheet-shaped carrier member
- 140: cell culture carriers
- 142: first connecting portion
- 144: second connecting portion
- 146: third connecting portion
- 150: turbulent part
- 160A, 160B, 160K: magnetic control part
- 170: fastener
- 180: rod
- 182: guide hole
- 190: fluid pressure control part
- C10: chamber
- D: moving direction
- T12, T14, T16, T18, T21, T23: inlet/outlet
- 1000, 2000: cell culture system
- 200: cell tank
- 300: culture medium module
- 310: culture medium tank
- 312: stirring bar
- 314: culture medium sensor
- 320, 500: pump
- 330, 900: regulator
- 400, 400A: cell culture module
- 600: cleaning solution tank
- 700: cell detachment enzyme tank
- 800: controller
- S110-S170: step
Claims (23)
- A cell culture module (100H-100N, 400A), comprising:a casing (111) having a chamber (C10) and at least one inlet/outlet (T12, T14, T16, T18, T21, T23), wherein the at least one inlet/outlet (T12, T14, T16, T18, T21, T23) communicates with the chamber (C10), the casing (111) is a six-sided box-shaped shape;a first fixer (120) fixed to the casing (111) and located in the chamber (C10);a second fixer (130, 130K, 130L) disposed in the chamber (C10) and being movable relative to the first fixer (120); anda sheet-shaped carrier member (14) formed by arranging a plurality of cell culture carriers (140) having straight strip shape and in linear arrangement, wherein two opposite ends of the sheet-shaped carrier member (14) are respectively fixed to the first fixer (120) and the second fixer (130, 130K, 130L), and the sheet-shaped carrier member (14) is in a stretched state or a folded state according to a variation in a distance between the first fixer (120) and the second fixer (130, 130K, 130L) due to a movement of the second fixer (130, 130K, 130L).
- The cell culture module (100H-100N, 400A) according to claim 1, wherein the plurality of cell culture carriers (140) are respectively fixed to the first fixer (120) and the second fixer (130, 130K, 130L) at two opposite ends of an axial extending direction.
- The cell culture module (100I-100N, 400A) according to claim 1, wherein the sheet-shaped carrier member (14) further comprises a first connecting portion (142) and a second connecting portion (144), two opposite ends of the plurality of cell culture carriers (140) are respectively fixed to the first connecting portion (142) and the second connecting portion (144), and the first connecting portion (142) and the second connecting portion (144) are adjacently connected to the first fixer (120) and the second fixer (130, 130K, 130L).
- The cell culture module (100I-100N, 400A) according to claim 3, wherein the first connecting portion (142) and the second connecting portion (144) have a zigzag or wavy shape.
- The cell culture module (100J-100N, 400A) according to claim 3, wherein the sheet-shaped carrier member (14) further comprises a third connecting portion (146) disposed between the first connecting portion (142) and the second connecting portion (144), such that one end of the plurality of cell culture carriers (140) is fixed to the first connecting portion (142) and another end of the plurality of cell culture carriers (140) is extended to the third connecting portion (146) and then extended to the second connecting portion (144) via the third connecting portion (146).
- The cell culture module (100I-100N, 400A) according to claim 1, wherein a moving direction of the second fixer (130) is perpendicular to an axial extending direction of the plurality of cell culture carriers (140) in the sheet-shaped carrier member (14).
- The cell culture module (100H-100N, 400A) according to claim 1, wherein the casing (111) has a tapered portion (113) and the at least one inlet/outlet (T12, T14, T16, T18, T21, T23) is disposed at the tapered portion (113).
- The cell culture module (100H-100N, 400A) according to claim 7, wherein number of the at least one inlet/outlet (T12, T14, T16, T18, T21, T23) is plural and the inlets/outlets (T12, T14, T16, T18, T21, T23) are respectively disposed at the tapered portion (113) and another side of the casing (111) opposite to the tapered portion (113).
- The cell culture module (100K, 400A) according to claim 1, further comprising a magnetic control part (160K), wherein the second fixer (130B, 130K) has magnetism and the magnetic control part (160K) is configured to magnetically control the second fixer (130B, 130K) to move.
- The cell culture module (100L, 400A) according to claim 1, further comprising a fastener (170), wherein the casing (111) further has an elastic corrugated structure (111A), the fastener (170) is configured to control the elastic corrugated structure (111A) to switch between a stretched state and a compressed state, the second fixer (130C, 130L) is fixed to the casing (111) and the elastic corrugated structure (111A) is located between the first fixer (120) and the second fixer (130C, 130L),when the elastic corrugated structure (I I I A) is in the stretched state, the sheet-shaped carrier member (14) is in the open state, andwhen the elastic corrugated structure (111A) is in the compressed state, the sheet-shaped carrier member (14) is in the folded state.
- The cell culture module (100M, 400A) according to claim 1, further comprising a rod (180) movably inserted through the casing (111) and connected to the second fixer (130, 130A) to control the second fixer (130, 130A) to move.
- The cell culture module (100N, 400A) according to claim 1, further comprising a fluid pressure control part (190) disposed at the casing (111) and located in the chamber (C10), wherein the second fixer (130, 130A) is located between the fluid pressure control part (190) and the first fixer (120) and the fluid pressure control part (190) is configured to control the second fixer (130, 130A) to move.
- A cell culture system, comprising:a cell tank (200);a culture medium module (300); anda cell culture module (100H-100N, 400A) selected from the cell culture module (100H-100N, 400A) according to claims 1 to 12, wherein the cell tank (200) and the culture medium module (300) respectively communicate with the cell culture module (100H-100N, 400A).
- The cell culture system according to claim 13, further comprising a pump (500), wherein the cell tank (200) and the culture medium module (300) respectively communicates with the cell culture module (100H-100N, 400A) via the pump (500).
- The cell culture system according to claim 13, further comprising a cleaning solution tank (600) communicated with the cell culture module (100H-100N, 400A).
- The cell culture system according to claim 13, further comprising a cell detachment enzyme tank (700) communicated with the cell culture module (100H-100N, 400A).
- The cell culture system according to claim 13, further comprising a controller (800), wherein the controller (800) is connected to the cell tank (200), the culture medium module (300) and the cell culture module (100H-100N, 400A).
- A cell culture method adopting the cell culture module (100H-100N, 400A) selected from the cell culture module (100H-100N, 400A) according to claims 1 to 12, comprising the steps ofattaching cells on the sheet-shaped carrier member (14) in the folded state;perfusing and circulating a culture medium in the cell culture module (100H-100N, 400A) and starting a cell culture;discharging the culture medium and perfusing a cleaning solution and performing an immersion and cleaning to remove a remaining culture medium;perfusing a cell detachment enzyme, and when the sheet-shaped carrier member (14) is in the open state, desorbing the cells from the sheet-shaped carrier member (14) to be suspended in a suspension of the cell culture module (100H-100N, 400A); andcollecting the suspension containing the cells.
- The cell culture method according to claim 18, wherein the step of attaching the cells to the sheet-shaped carrier member (14) in the folded state further comprises: rendering the sheet-shaped carrier member (14) of the cell culture module (100H-100N, 400A) to the folded state first and then inoculating the cells on the sheet-shaped carrier member (14) in the folded state.
- The cell culture method according to claim 18, wherein the step of attaching the cells on the sheet-shaped carrier member (14) in the folded state further comprises: inoculating the cells on the sheet-shaped carrier member (14) in the open state and rendering the sheet-shaped carrier member (14) of the cell culture module (100H-100N, 400A) to the folded state.
- The cell culture method according to claim 18, wherein the step of attaching the cells on the sheet-shaped carrier member (14) in the folded state further comprises: moving the second fixer (130, 130K, 130L) to a position close to the first fixer (120), so that the sheet-shaped carrier member (14) of the cell culture module (100H-100N, 400A) is in the folded state.
- The cell culture method according to claim 18, wherein the step of perfusing the cell detachment enzyme and desorbing the cells from the sheet-shaped carrier member (14) to be suspended in the suspension of the cell culture module (100H-100N, 400A) when the sheet-shaped carrier member (14) is in the open state further comprises: perfusing the cell detachment enzyme first and then transforming the sheet-shaped carrier member (14) from the folded state to the open state.
- The cell culture method according to claim 18, wherein the step of perfusing the cell detachment enzyme and desorbing the cells from the sheet-shaped carrier member (14) to be suspended in the suspension of the cell culture module (100H-100N, 400A) when the sheet-shaped carrier member (14) is in the open state further comprises: transforming the sheet-shaped carrier member (14) from the folded state to the open state first and then perfusing the cell detachment enzyme.
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US201762610909P | 2017-12-27 | 2017-12-27 | |
TW107145323A TWI679277B (en) | 2017-12-27 | 2018-12-14 | Cell culture module, cell culture system and cell culture method |
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EP3505613A1 EP3505613A1 (en) | 2019-07-03 |
EP3505613B1 true EP3505613B1 (en) | 2024-07-03 |
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EP18213492.4A Active EP3505613B1 (en) | 2017-12-27 | 2018-12-18 | Cell culture module, cell culture system and cell culture method |
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EP (1) | EP3505613B1 (en) |
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WO2022115033A1 (en) * | 2020-11-24 | 2022-06-02 | Turtletree Labs Pte. Ltd. | Bioreactor systems and methods for culturing cells |
CN112980649A (en) * | 2021-03-04 | 2021-06-18 | 江南大学 | Hollow tube bundle type fixed bed bioreactor for adherent culture of breast-feeding cells |
US11752509B2 (en) | 2021-06-17 | 2023-09-12 | Upside Foods, Inc. | Fluid dispenser for recovering material from a surface |
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US5266476A (en) | 1985-06-18 | 1993-11-30 | Yeda Research & Development Co., Ltd. | Fibrous matrix for in vitro cell cultivation |
US6121042A (en) * | 1995-04-27 | 2000-09-19 | Advanced Tissue Sciences, Inc. | Apparatus and method for simulating in vivo conditions while seeding and culturing three-dimensional tissue constructs |
US5686304A (en) | 1995-12-15 | 1997-11-11 | Avecor Cardiovascular, Inc. | Cell culture apparatus and method |
US6245557B1 (en) * | 1999-06-30 | 2001-06-12 | Robert P. Fouts | Cell and protein harvesting assemblies and methods |
US7585323B2 (en) * | 2000-05-05 | 2009-09-08 | Medlden, Llc | In vitro mechanical loading of musculoskeletal tissues |
EP1465978B1 (en) * | 2002-01-15 | 2006-09-20 | Biogentis Inc. | Method and apparatus for inducing controlled mechanical constraints in a tissue construct |
US7033823B2 (en) | 2002-01-31 | 2006-04-25 | Cesco Bioengineering, Inc. | Cell-cultivating device |
WO2008089510A1 (en) | 2007-01-22 | 2008-07-31 | Ian Malcolm Wright | A variable volume bioreactor |
DE102007038777A1 (en) | 2007-08-10 | 2009-02-19 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Cell culture measuring system and method for comparative studies on cell cultures |
CN101748063A (en) | 2010-01-08 | 2010-06-23 | 杭州安瑞普生物科技有限公司 | Culture apparatus and applications thereof in cell culture |
US9453197B2 (en) | 2010-12-16 | 2016-09-27 | General Electric Company | Methods of making cell carrier |
CN203048948U (en) | 2012-10-17 | 2013-07-10 | 浙江赛尚医药科技有限公司 | Cell culture piping device and cell automated culture system |
JP6153357B2 (en) * | 2013-03-22 | 2017-06-28 | 株式会社スペース・バイオ・ラボラトリーズ | Cell culture vessel |
EP3114206B1 (en) | 2014-03-04 | 2020-07-29 | Pluristem Ltd. | Systems and methods for growing and harvesting cells |
WO2016063364A1 (en) * | 2014-10-22 | 2016-04-28 | 株式会社日立ハイテクノロジーズ | Cytometric mechanism, cell culture device comprising same, and cytometric method |
TWI672375B (en) * | 2015-12-09 | 2019-09-21 | 財團法人工業技術研究院 | Cell culture carrier module, bioreactor and cell recovery method |
EP3455339B1 (en) * | 2016-05-11 | 2020-11-25 | Corning Incorporated | Structured bag for cell culture |
CN108384717A (en) | 2017-02-03 | 2018-08-10 | 财团法人工业技术研究院 | Cell culture carrier module and cell culture system |
WO2019060218A1 (en) * | 2017-09-19 | 2019-03-28 | Life Technologies Corporation | Systems and methods for a collapsible chamber with foldable mixing element |
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US11254902B2 (en) | 2022-02-22 |
CN109971645A (en) | 2019-07-05 |
EP3505613A1 (en) | 2019-07-03 |
JP6936782B2 (en) | 2021-09-22 |
US20190203165A1 (en) | 2019-07-04 |
JP2019141034A (en) | 2019-08-29 |
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